rs28943591

Variant names:

• chr5-119515014-G-A
• rs28943591
• NM_000414.4:c.1471G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-119515014-G-A
• chr5-119515014-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000414.4(HSD17B4):​c.1471G>A​(p.Ala491Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00495 in 1,585,784 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (23 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 3.84
• Publications: 14 publications found

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

HSD17B4 Gene-Disease associations (from GenCC):

• d-bifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012981385).
• BP6: Variant 5-119515014-G-A is Benign according to our data. Variant chr5-119515014-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00355 (540/152178) while in subpopulation NFE AF = 0.00618 (420/67970). AF 95% confidence interval is 0.00569. There are 2 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.1471G>A	p.Ala491Thr	missense	Exon 17 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.1546G>A	p.Ala516Thr	missense	Exon 18 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.1462G>A	p.Ala488Thr	missense	Exon 17 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1471G>A	p.Ala491Thr	missense	Exon 17 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.1402G>A	p.Ala468Thr	missense	Exon 17 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.1546G>A	p.Ala516Thr	missense	Exon 18 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152060 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00344 AC: 864 AN: 251252 AF XY: 0.00348

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00509 AC: 7303 AN: 1433606 Hom.: 23 Cov.: 25 AF XY: 0.00499 AC XY: 3566 AN XY: 715194

African (AFR) AF: 0.000912 AC: 30 AN: 32888

American (AMR) AF: 0.00521 AC: 233 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000617 AC: 16 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85670

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53404

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5696

European-Non Finnish (NFE) AF: 0.00620 AC: 6734 AN: 1086428

Other (OTH) AF: 0.00410 AC: 244 AN: 59474

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152178 Hom.: 2 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74390

African (AFR) AF: 0.000939 AC: 39 AN: 41540

American (AMR) AF: 0.00445 AC: 68 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00618 AC: 420 AN: 67970

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00495 Hom.: 1

Bravo AF: 0.00418

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00311 AC: 378

Asia WGS AF: 0.000289 AC: 1 AN: 3470

EpiCase AF: 0.00780

EpiControl AF: 0.00711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	2	Bifunctional peroxisomal enzyme deficiency (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
-	-	1	Perrault syndrome 1 (1)
-	-	-	Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.098	T
Sift4G	Benign	0.24	T
Polyphen		0.62	P
Vest4		0.37
MVP		0.90
MPC		0.12
ClinPred		0.039	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.76
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28943591; hg19: chr5-118850709;